Qiu Jian, Voliotis Margaritis, Bosch Martha A, Li Xiao Feng, Zweifel Larry S, Tsaneva-Atanasova Krasimira, O'Byrne Kevin T, Rønnekleiv Oline K, Kelly Martin J
Department of Chemical Physiology and Biochemistry, Oregon Health & Science U., Portland, OR 97239, USA.
Department of Mathematics and Statistics, University of Exeter, Stocker Rd, Exeter, EX4 4PY, UK.
bioRxiv. 2024 Sep 3:2024.02.20.581121. doi: 10.1101/2024.02.20.581121.
Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1) neurons are responsible for the pulsatile release of Gonadotropin-releasing Hormone (GnRH). In females, the behavior of Kiss1 neurons, expressing Kiss1, Neurokinin B (NKB), and Dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increases mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current and that contribute to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of Canonical Transient Receptor Potential (TPRC) 5 and G protein-coupled K (GIRK) channels. When TRPC5 channels in Kiss1 neurons were deleted using CRISPR, the slow excitatory postsynaptic potential (sEPSP) was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of the Kiss1 neuron, suggesting that E2 modifies ionic conductances in Kiss1 neurons, enabling the transition from high frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1 neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.
下丘脑促性腺激素释放激素神经元（Kiss1）对青春期发育和生殖至关重要。弓状核Kiss1（Kiss1）神经元负责促性腺激素释放激素（GnRH）的脉冲式释放。在雌性动物中，表达Kiss1、神经激肽B（NKB）和强啡肽（Dyn）的Kiss1神经元的行为在整个卵巢周期中会发生变化。研究表明，17β-雌二醇（E2）可降低这些神经元中的肽表达，但会增加mRNA和谷氨酸神经传递，这表明从肽能信号传导转变为谷氨酸能信号传导。为了研究这种转变，我们结合了转录组学、电生理学和数学建模。我们的结果表明，E2处理可上调电压激活钙通道的mRNA表达，增加全细胞钙电流，并导致高频爆发式放电。此外，E2处理降低了经典瞬时受体电位（TRPC）5和G蛋白偶联钾（GIRK）通道的mRNA水平。当使用CRISPR删除Kiss1神经元中的TRPC5通道时，慢兴奋性突触后电位（sEPSP）消失。我们的数据使我们能够构建一个Kiss1神经元的生物物理真实数学模型，表明E2改变了Kiss1神经元中的离子电导，从而实现了从通过NKB驱动的TRPC5通道激活的高频同步放电到促进谷氨酸释放的短爆发模式的转变。在低E2环境中，Kiss1神经元的同步放电驱动GnRH的脉冲式释放，而在排卵前高水平E2时转变为爆发式放电将通过其与视前区Kiss1神经元的谷氨酸能突触连接促进GnRH激增。
